Abstract

The lack of an efficient pre-clinical model predicting a drug's clinical response before it enters into clinical trials is a major reason behind the limited success or complete failure of most of the traditional anti-cancer compounds. In this study, we evaluate our novel, safe and selective STAT3 inhibitor HO-3867 for its anti-cancer efficacy/bio-availability using a pre-clinical relevant, orthotopic ovarian tumor model and ex-vivo human tumor tissue culture. Treatment with HO-3867 (100PPM) significantly suppressed ovarian tumor growth and metastasis when compared to the standard Cisplatin (4mg/kg). A substantial amount of HO-3867 was detected in the ovarian tumor tissues and quantified using EPR spectroscopy. Markers specific to cell proliferation (Ki-67, Cyclin D1), angiogenesis (VEGF and Kinase array) and apoptosis (caspase-3 activity) were significantly altered by treatment with HO-3867. In vivo histopathological evaluation of internal organs collected from treated tumor mice revealed no evidence of toxicity specific to HO-3867. Normal and malignant tissues were collected and TUNEL/8-OHdG staining revealed selective induction of apoptosis limited to neoplastic cells and concomitant increase in reactive oxygen species within the orthotopic tumor. Suppression of STAT3 and its downstream target proteins (cell proliferative, anti-apoptotic and angiogenic) was confirmed with proteomic array. HO-3867 treated samples had significantly reduced vessel formation (∼4 times) as compared to the untreated control as is evident by in vivo Matrigel assay. HO-3867 was also found to have cytotoxic effects in ex vivo culture of freshly collected human tumor samples, including patients with chemotherapy resistant form of the disease. Overall, these results highlight the clinical anti-cancer potential of HO-3867 using a relevant preclinical orthotopic ovarian tumor model, and provide a rationale for the inclusion of ex vivo patient tumor slice culture in oncologic drug development processes.